CZ299411B6 - Pharmaceutical hydrophilic gel forming matrix formulation and process for preparing thereof - Google Patents

Abstract

The present invention relates to an optionally coated pharmaceutical hydrophilic gel forming matrix formulation comprising one or more active substances and having a prolonged release of said one or more active substances upon exposure to gastrointestinal fluids, characterized in that said release of the active substance(s) is substantially ion-strength independent. The invention further relates to a process for preparing such formulation, which can be used in the administration of active substances for the treatment of a large number of diseases.

Description

(57)

The invention relates to a pharmaceutical matrix preparation, optionally coated, forming a hydrophilic gel comprising one or more active substances and, upon exposure to gastrointestinal juices, exhibiting a sustained release of one or more active substances, the active substance (s) being substantially independent of ionic power. The invention further relates to a process for the manufacture of such a composition which can be used for the administration of active substances for the treatment of a large number of diseases.

(O

Z 299411

A pharmaceutical matrix formulation forming a hydrophilic gel and a process for making the formulation

Technical field

The present invention relates to a pharmaceutical composition that behaves essentially as a sustained (modified) composition wherein the release is independent of the ionic strength of the dissolution medium, e.g., gastrointestinal juice. Prolonged release is achieved up to 16 hours. The pharmaceutical composition of the invention combines one or more active ingredients with a mixture of carrier hydrophilic polymers to form a gel-forming matrix composition.

BACKGROUND OF THE INVENTION

Hydrophilic gel matrix formulations (dosage forms) are well known dosage forms that are used to modify or control the dissolution behavior of an active agent. The mechanism by which the active ingredient is released begins by hydrating the surface of the dosage form and forming a gel structure. At the same time, the active ingredient dissolves on the surface of the dosage form in a dissolution medium. In the stationary phase, the dissolution medium continuously penetrates the gel structure and the gel expands. The active substance dissolves in the dissolution medium and is transported to the outer layer of the gel. At the same time, erosion of the outer gel layer occurs. Finally, the release level is stabilized due to the decreasing concentration gradient of the active ingredient in the dosage form and the penetrating dissolution medium. This mechanism has been described in the art, see e.g. Manford Robinson, The Theory and Practice of Industrial Pharmacy, ^2nd Edition, Chapter 14: "Sustained Action Dosage Forms".

The hydrophilic polymers used in the above-described dosage forms are mostly polysaccharide carriers such as cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (NaCMC) or combinations of these cellulose derivatives.

The dosage forms thus formulated have been described, for example, in many patents and patent applications, e.g., in US 4,871,548 and EP-A-0 923 934.

US 4,871,548 discloses a sustained release dosage form comprising the active compound and a mixture of at least a low viscosity cellulose ether with a high viscosity cellulose ether. EP-A-0 923 934 discloses a modified release matrix form of cefaclor and cephalexin comprising a 5% to 35% blend of hydrophilic polymers of various grades, wherein the hydrophilic polymers contain about 0.1% to about 20% (by weight) of medium viscosity hydroxypropylmethylcellulose and about 0.1% to about 20% of low viscosity hydroxypropylcellulose.

Although the above-described dosage forms have been described as modified / pro45 sustained release dosage forms generally, sustained release occurs only when the salt concentration, i.e. the ionic strength, in the dissolution medium is low. The release rate (liberation) of the active ingredient from the above dosage forms is strongly dependent on the ionic strength. High ionic strength can even lead to so-called 'dose-dumping'. In this case, the entire amount of the active ingredient is released in a very short time, which can lead to undesirable, and sometimes to the end, dangerous, high levels of the active ingredient in the blood. High ionic strength often occurs directly after ingestion of food. Since patients often take drugs just after a meal, there is a significant risk that a dosage form in which drug release is dependent on ionic strength will lead to undesirable rapid release of the active ingredient instead of the desired sustained release.

-1 CZ 299411 B6

WO 98/47 491 discloses a sustained release dosage form wherein the release control of the active ingredient is based on a combination of two so-called "smart" polymers having opposing wettability characteristics where one polymer has a stronger tendency to hydrophobicity and the other has a stronger tendency to hydrophilicity. In such a dosage form, rapid release of the drug dose can only be prevented by coating with an enteric coating.

It was therefore an object of the present invention to provide a sustained release pharmaceutical formulation wherein the sustained release is substantially independent of the ionic strength of the dissolution medium, which is normally gastrointestinal juice, even if the dosage form is not coated. The skilled artisan will appreciate that such a dosage form must additionally meet normal physical and pharmaceutical requirements in the art, such as good flow characteristics of the tablets for tabletting, compressive strength of the compressed tablet of at least 30 N, friability of less than 1% at compressive pressure between 10 and 40. kN, uniformity of content and sufficient stability.

A further requirement is that the dosage form can be prepared by conventional formulation techniques using commonly used equipment so that no major investment is required in manufacturing.

SUMMARY OF THE INVENTION

The object of the invention was achieved by providing a hydrophilic gel-forming matrix pharmaceutical composition which exhibits a sustained release of one or more active agents upon exposure to gastrointestinal juice, wherein the sustained release is substantially independent of ionic strength.

Sustained release is defined as the (sustained) release of the active ingredient from a preparation / dosage form over a period of 45 minutes or longer. This release period usually begins with administration of the dosage form or, in the case of an in-vitro dissolution test, begins with the initiation of the test (at the time the dosage form is brought into contact with the dissolution medium).

By "substantially independent of ionic strength" it is meant that the rate of release of the active substance is not significantly altered (according to the US Pharmacopoeia, General Chapter 711: Physical Tests and Determinations in USP 24 (± 10% declared quantity) when the ionic strength (I) is changed between 0.05 and 0.45 mol / l The ionic strength (I) is defined by the equation: I = ΆΣοζ, ² , where c is the concentration of different ions in solution and Zj their corresponding charge (Handbook of Chemistry and Physics 71 ^st edition

David R. Lide ed., Page 2-18, Boston, CRC Press Inc., 1990-1991).

Although coating is not necessary to achieve independence from ionic strength, the dosage forms are optionally coated with a coating material to achieve the other desired effect, such as taste masking or a suitable application color. Suitable coatings are known to those skilled in the art and include, for example, HPMC, acrylates, ethylcellulose (see Graham Cole ed., Pharmaceutical Coating Technology, London, Taylor & Francis Ltd., 1995).

The hydrophilic gel-forming matrix is in the form of a tablet or a multi-component dosage form, and preferably comprises a mixture of at least two hydrophilic cellulose ethers of high viscosity. Although the presence of hydrophobic cellulose ethers such as ethylcellulose would normally have no deleterious effect on release from the dosage form, preferably no significant amount of hydrophobic cellulose ether is present. By significant amount of hydrophobic cellulose ether is meant an amount greater than 20% of the total weight of the gel forming polymers.

Cellulose ethers are known to those skilled in the art and are available in a pharmaceutical grade of different average molecular weights which cause different viscosities of solutions of these cellulose ethers. For the purpose of the present patent application, hydrophilic polymers can be characterized by their viscosity in a 2% (w / w) aqueous solution as having a low viscosity (less than about 1000 mPa.s), a medium viscosity (about 1000 mPa.s to about 10 m / s). And high viscosity (greater than about 10,000 mPa.s).

-2GB 299411 B6

Hydrophilic hydroxypropyl methylcellulose (HPMC) polymers that can be used in the present invention are available in different viscosity grades from Dow Chemical Co. Under the Methocel® trademark and from Shin Etsu under the Metolose® trademark.

Examples of low viscosity polymers are Methocel E5®, Methocel E-15LV®, Methocel E50LV®, Methocel K100LV® and Methocel F50LV®, whose 2% aqueous solutions at 25 ° C had viscosities of 5 mPa.s, 15 mPa.s, 50 mPa.s, 100 mPa.s, and 50 mPa.s, respectively.

Examples of medium viscosity HPMCs are Methocel E4M® and Methocel K4M, whose 2% aqueous solutions at 25 ° C had a viscosity of 4000 mPa.s.

Examples of high viscosity HPMCs are Methocel K15M® and Methocel K100M®, whose 2% aqueous solutions at 25 ° C have viscosities of 15,000 mPa · s and 100,000 mPa · s respectively.

Hydrophilic polymers of hydroxyethylcellulose (HEC) that can be used in the present invention are available in various viscosity grades from AQUALON under the trademark Natrosol® and from Amerchol Corporation under the trademark Cellosize®.

Examples of low viscosity polymers are Natrosol L® and Natrosol J®, whose 2% aqueous solutions at 25 ° C had viscosities of 10 mPa.s and 20 mPa.s, respectively.

Examples of medium viscosity polymers are Natrosol G® and Natrosol K®, whose 2% aqueous solutions at 25 ° C had viscosities of 200 mPa · s and 1500 mPa · s respectively.

Examples of high viscosity polymers are Natrosol M® and Natrosol HH®, whose 2% aqueous solutions had viscosities at 25 ° C of 4000 mPa · s and 90 000 mPa · s respectively.

SUMMARY OF THE INVENTION The present invention provides a hydrophilic gel-forming pharmaceutical matrix composition comprising one or more active ingredients and exhibiting sustained release of one or more active ingredients upon exposure to gastrointestinal juices comprising high or medium viscosity hydroxypropyl methylcellulose (HPMC) and high hydroxyethylcellulose (HEC). or medium viscosity, at a ratio of HPMC / HEC = 1 / 0.85 to 1 / 1.2, and optionally a low viscosity HPMC, wherein the ratio of high or medium viscosity HPMC / low viscosity HPMC - 1 / 0.01 to 1 / 0.2.

In a preferred embodiment of the present invention, the ratio between high or medium viscosity HPMC and high or medium viscosity HEC is 1 / 0.9 to 1 / 1.1, even more preferably is 1 / 0.95 to 1 / 1.05, and most preferably is 1/1. The formulations may optionally contain a low viscosity HPMC.

in such a case, the ratio between high or medium viscosity HPMC and low viscosity HPMC is preferably 1 / 0.01 to 1 / 0.1, even more preferably 1 / 0.02 to 1 / 0.05.

Surprisingly, it has been found that formulations having the above composition can be used to produce tablets having a release rate that is independent of ionic strength within the range normally found in gastrointestinal juice. This normal range is between 0.17 and 0.35 mol / L.

In addition to being independent of ionic strength, the principle controlling release from the formulation is also substantially pH independent in the range between pH = 1.3 and pH 7.4. This means that the release rate of the active substance is not affected by the pH in those cases where the release of the active substance is not limited by the permeability of the active substance, ie when the differences in release value (in%) at a given moment are less than 20% of the declared value Dissolution Specifications (page 1080-81) in FIP Guidelines for Dissolution Testing of Solid Oral Products (Draft Final, 1995), Drug Information Journal 1996, Vol 30, 1071-84) across the pH range between 1.3 and 7.4 .

-3 CZ 299411 B6

Due to the optimal properties of the pharmaceutical composition as a sustained release formulation, the composition of the present invention can be used in the treatment of a variety of diseases in cases where sustained release of the active ingredient is desired. Examples of the active agent that can be formulated in sustained release dosage forms include active agents for treating CNS disorders including schizophrenia, episodic anxiety attacks (episodic paroxysmal anxiety (EPA)) such as obsessive compulsive disorder (OCD), post-traumatic stress (PTSO), phobias and panic, major depressive disorder, bipolar disorder, Parkinson's disease, general anxiety (anxiety), autism, delirium, multiple sclerosis, Alzheimer's disease / dementia and other neurodegenerative diseases, severe mental retardation, dyskinesias such as Huntington's disease or Gilles cannons Tourette's syndrome, anorexia, bulimia, stroke, addiction / dependence / craving, sleep disorders, epilepsy, migraine, attention deficit / hyperactivity (ADHD), cardiovascular diseases including heart failure, angina pectoris, arrhythmias, myocardial infarction, heart hypertrophy, hypotension, hyper tension such as essential hypertension, renal hypertension or pulmonary hypertension, thrombosis, arteriosclerosis, cerebral vascular spasms, subarachnoid haemorrhage, cerebral ischemia, cerebral infarction, peripheral vascular disease, Raynaud's disease, kidney disease, renal failure, obesity, emesis, dementia ), gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastroesophageal reflux (GERD), motility disorders and delayed gastric emptying, such as postoperative or diabetic gastro20 paresis, diabetes, ulcers - e.g., gastric ulcer, diarrhea , and other diseases such as osteoporosis, gynecological disorders, inflammation, infections such as bacterial, fungal, protozoal and viral infections, specifically HIV-1 or HIV-2 infections, pain, cancer, chemotherapy-induced damage, tumor invasion, immune disorders, urinary retention, asthma, allergies, arthritis ida, benign prostatic hypertrophy, endotoxin shock, sepsis, complications in diabetes mellitus.

Preferred active ingredients for the pharmaceutical compositions of the invention are those used to treat CNS disorders, such as fluvoxamine (O- (2-aminoethyl) oxime-5-methoxy-1- [4 (trifluoromethyl) phenyl] -1 -pentanone) or flesinoxane (N- [2- [4 - [(2R) -2,3-dihydro-2- (hydroxymethyl) -1,4-benzodioxin-5-yl] -1-piperazinyl] ethyl] -4 -fluoro - (+) - benzamide), for the treatment of cardio30 vascular diseases such as tedisamil (N, N'-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane) or propanolol, or active substances which are used in the treatment of gynecological disorders, such as hormone replacement therapy, such as dydrogesterone, estradiol or conjugated estrogens. The present invention is particularly useful for formulations of the active substance flesinoxane, in particular in the form of the monohydrochloride (N- [235 [4 - [(2R) -2,3-dihydro-2- (hydroxymethyl) -1,4-benzodioxin-5-yl) hydrochloride] ] -1-piperazinyl] ethyl] -4-fluoro - (+) benzamide) described in EP 0 307 280 and EP 307 061 and tedisamil, preferably in the form of a sesquifumarate (N, N'-dicyclopropylmethyl-9,9- tetramethylene-3,7-diazabicyclo [3.3.1] nonane- [1,5] hydrogen fumarate) described in EP 0 550 383.

The present invention also relates to a process for the preparation of a composition according to the invention, comprising (1) compressing a core from a mixture comprising one or more active ingredients and high or medium viscosity hydroxypropylmethylcellulose (HPMC) and high or medium hydroxyethylcellulose (HEC) viscosity, at a ratio of HPMC / HEC = 1 / 0.85 to 1 / 1.2, and optionally a low viscosity HPMC, wherein the ratio of high or medium viscosity HPMC / low viscosity HPMC is 1 / 0.01 to 1 / 0.2, which provides sustained release of the active agent, essentially with zero order kinetics, and (2) optionally, the core is coated.

The components HPMC, HEC, active ingredient, glidant mixture are mixed in a suitable mixer. This powder mixture is then mixed with sodium stearyl fumarate in a suitable mixer. The active ingredient can be added to the powder mixture in the form of pre-granulated and then used for compression. Alternatively, the powder mixture for tabletting may be formed by a mixing process followed by granulation (wet or dry).

-4GB 299411 B6

The mixture of ingredients is compressed into tablets using a commercially available device (e.g., Courtoy® RO) using flow-regulating agents such as colloidal silica and lubricants such as talc, sodium stearyl fumarate or magnesium stearate. The amount of hydrophdic celluloses in the complete formulation is in the range of 15% to 99.5%, while the amount of active agent is in the range of 0.1% to

80%. The amount of flow control agents and lubricants is determined to improve the flow properties of the powder and prevent adhesion of the powder to the color wall or dies. The amount of glidant is in the range 0.05% to 5% and preferably is about 0.2%. The amount of lubricant is in the range of 0.05% to 5% and preferably is about 0.4%. For commercial reasons, the powder mixture can be colored by admixing 0.1% to 10% dye. Typical dye mixtures are commercially available, e.g., Opadry® from COLORCON®.

All published documents, including patents and patent applications, cited in the present application are incorporated herein by reference, unless specifically indicated for each individual publication.

The following examples are intended to illustrate and explain the invention in more detail, and do not limit the scope of the present invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Formulation of a pharmaceutical composition with ionic strength independent release

Example 1a

General preparation procedure

First, the colloidal silica was filtered through a sieve. Preferably through a sieve with a grid between 0.40 mm to 0.595 mm. The active ingredient was then mixed together with hydrophilic celluloses, colloidal silica, a dye mixture and, if necessary, mannitol, in a suitable mixer. Preferably, a high shear mixer and a granulator in the off position were used. The stearyl fumarate was also filtered through a sieve. Preferably through a sieve with a grid between 0.40 mm to 0.595 mm.

The powder mixture was then compressed into tablets of the desired size. A rotary press, such as Korsch and Courtoy equipment, was preferably used for the molding. Optionally, the tablets may be coated with water-soluble cellulose or cellulose derivatives, such as ethylcellulose, or acrylates in the form of an aqueous suspension or in organic solvents. The coating is preferably carried out in a perforated coating drum or fluidized bed technology.

-5GB 299411 B6

Table 1

Preparation in the form of uncoated tablets (tablet cores), values given in mg / tablet.

Material Flesino- xan Deklar. amount: 2 mg / t Acetami- nofen Deklar. amount: 2.2 mg / t Fluvoxa- min maleate Deklar. amount: 100 mg / t Tedisa- mil. diHCl Deklar. amount: 100 mg / t Tedisa- mil seskvi- fumarate Deklar. amount: 150 mg / t Flesinoxan.HCI 2.18 on. on. on. on. Acetaminophen on. 2.19 on. on. on. Fluvoxamine maleate on. on. 100.00 on. on. Tedisamil.diHCl on. on. on. 124.4 on. Tedisamil.seskvifum on. on. on. on. 240.0 HPMC K4M 69, 63 69, 63 17.00 125.2 81.0 HPMC E5 7.50 7.50 12.50 20.0 14.0 HEC HX250PH 69.63 69.63 17.00 125.2 81.0 Manitol SD200 on. on. 100.00 on. on. Colloidal silica oxide. 0, 30 0, 30 0.50 1, 60 4.0 Mixture of dyes PB23015 0.15 0.15 on. 0.40 on. Stearyl fumarate Na 0.60 0.60 3.00 3.20 5.0 total weight tablets (mg) 150.00 150.00 250.00 400.00 425.00

n.a .: not applicable

Table 2

Properties of some preparations

Property tablets Flesino Deklar. amount: 2 mg / t Acetami- nofen Deklar. amount: 2.2 mg / t Fluvox-min maleate Deklar. amount: 100 mg / t coated Tedis-mil. diHCl Deklar. amount: 100 mg / t Tedis-mil seskvi- fumarate Deklar. amount: 150 mg / t Dimensions tablets (mm) 5,5 X 11,0 mm specially shaped 7,0 mm round 8,0 mm round 8,0 x 15,0 mm oval 8,0 x 15,0 mm oval Mass tablets (mg) 150 150 275 400 425 Compressive strength (N) 83 75 144 71 90 Drolivost (%) Not specified Not specified Not specified 0.4 0, 05 Profile release (liberace) Tab, 4 Tab. 4 Tab. 4 Tab. 4 Tab. 4

-6GB 299411 B6

Example 1b

Release properties of the active substance from certain preparations

The release of the drug from the hydrophilic tablet matrix was measured using a USP dissolution apparatus II with paddles rotating at 50 rpm. (rpm) either in USP dissolution buffer with a mean pH of 6.8, 0.05 moles (M), 0.17 M and 0.34 M, prepared from sodium hydrogen phosphate with 2 H ₂ O and citric acid with 1H ₂ O (buffers) were marked with codes F, G and H respectively) or in half-exchange dissolution medium prepared from 0.1 M aqueous hydrochloride solution in the first part of the test (90 minutes), followed by 0.2 M with pH 6.8 adjusted with sodium phosphate with 12 H ₂ O in the second part of the test. Sodium chloride was added to the solution to increase the ionic strength of the aqueous solution during the assay. 1 liter of dissolution medium in Part Two contained the indicated amounts of sodium chloride, respectively: 0 grams (dissolution medium A),

10 grams (dissolution medium B), 15 grams (dissolution medium C), 30 grams (dissolution medium)

D1 and D2), and 50 grams (dissolution medium E1 and E2). In dissolution media B, C, D1 and E1, sodium chloride was added only in the second part of the assay. In D2 and E2 dissolution media, 75% sodium chloride was added in the first part of the assay and 25% in the second part of the assay. The drug release was measured for 16 hours with a sampling interval of one hour during the first two hours, followed by a sampling interval of two hours for the remaining duration of the test. Samples could be analyzed online using an HPLC system or UV spectroscopy. The release of various active compounds from the formulations is shown in Tables 4a to 4c.

From the data characterizing the release in Tables 4a to 4c, it can be concluded that the release of the active ingredient from the formulation of the present invention is substantially independent of pH and ionic strength since the differences in release are less than 20%. Furthermore, it can be concluded that there is no significant difference between the release profiles when the ionic strength is increased at low pH (pH 1.2) or at higher pH (pH 6.8).

Table 3

Overview of dissolution media

Method of dissolution Dissolution medium AND (B) C Dl D2 El E2 1) pH 1.2 1.5 hours 750 mL 0.1 M HCl NaCl added (g) 22.5 37.5 2) pH 6.8 14.5 hours 250 ml 0.2 M Na ₃ PO ₄ , 12 H ₂ O NaCl added (g) 0 10 15 Dec 30 7.5 50 12, 5 Ionic strength (mol / 1) in the resulting dissolution medium 0.14 0.31 0.40 0.65 0.65 1.00 1.00

-7EN 299411 B6

Method of dissolution Dissolution medium F G H pH 6.8 Na ₂ HPO ₄ , 2 H ₂ O + citric acid, 1 H ₂ O 0.05 M 0.17 M 0.34 M Ionic strength (mol / l) 0.11 0.38 0.77

Table 4a

Release from various preparations in the form of an uncoated tablet as a function of time

Amount of active substance (%) relaxed after interval Flesinoxan Deklar. amount: 2 mg / t Acetaminophen Deklar. amount: 2.2 mg / t Fluvoxamine maleate Deklar. amount: 100 mg / t dissolution medium AND (B) Dl El F G H AND (B) C 0 hours 0 0 0 0 0 0 0 0 0 0 1 hour 20 May 18 20 May 18 21 15 Dec 25 22nd 22nd 22nd 2 hours 32 28 31 30 34 29 38 36 36 35 6 hours 59 52 53 50 70 63 70 67 66 64 16 hours 91 84 83 79 107 105 103 99 99 99

Table 4b

Release from various preparations in the form of an uncoated tablet as a function of time

Amount of active substance (%) relaxed after interval Tedisamil.diHCl Deklar. amount: 100 mg / t Tedisamil sesquifumarate Deklar. amount: 150 mg / t dissolution medium AND (B) C AND Dl D2 El E2 0 hours 0 0 0 2 0 0 2 0 1 hour 32 32 33 20 May 18 20 May 20 May 21 2 hours 50 51 52 32 24 32 32 33 6 hours 84 85 84 47 45 49 47 52 16 hours 92 94 93 79 75 76 75 81

-8EN 299411 B6

Table 4c

Release of tedisamil sesquifumarate from uncoated tablets in simple dissolution medium as a function of time

Amount effectively Tedisamil sesquifumarate substances (%) Deklar. amount: 150 mg / t relaxed over time dissolution medium 750 ml 0.1 M HCl 750 mL 0.1 M HCl + (pH 1,2) 250 ml 0.2 M Na ₃ PO _{4 (} 12 H ₂ O (pH 6.8) 0 hours 0 0 1 hour 20 May 13 2 hours 33 22nd 6 hours 64 48 16 hours 97 89

Claims (12)

PATENT CLAIMS A pharmaceutical matrix formulation comprising a hydrophilic gel comprising one or more active ingredients and exhibiting a sustained release of one or more active ingredients upon exposure to gastrointestinal juices, characterized in that it contains high or medium viscosity hydroxypropyl methylcellulose (HPMC) and hydroxyethylcellulose ( HEC) with a high or medium viscosity at a ratio of HPMC / HEC = 1 / 0.85 to 1/1, 2, and optionally a low viscosity HPMC, wherein the ratio of high or medium viscosity HPMC / low viscosity HPMC = 1 / 0.01 to 1 / 0.2. A composition according to claim 1, characterized in that it is coated. Composition according to claim 1 or 2, characterized in that one or more active substances are selected from the group consisting of active substances for the treatment of CNS disorders, including diseases: schizophrenia, episodic seizure anxiety (EPA) such as obsessive com25 pulse disorder (OCD), post-traumatic stress disorder (PTSD), phobic disorder and panic attack, depression, bipolar disorder, Parkinson's disease, general anxiety disorder, autism, delirium, multiple sclerosis, Alzheimer's disease / dementia and other neurodegenerative diseases, severe mental retardation dyskinesias such as Huntington's disease or Gilles cannons Tourette's syndrome, anorexia, bulimia, stroke, addiction / addiction / craving, sleep disorders, 30 epilepsy, migraine, attention disorders / hyperactivity disorder (ADHD), cardiovascular disease including heart failure, angina pectoris, arrhythmias, myocardial infarction, cardiac hypertrophy, hypotension, hypertension - essential hypertension, renal hypertension or pulmonary hypertension, thrombosis, arteriosclerosis, arteriosclerosis, arteriosclerosis, arteriosclerosis , subarachnoid haemorrhage, cerebral ischemia, cerebral infarction, peripheral vascular disease, Raynaud's disease, disease Renal failure - renal failure, dyslipidemia, obesity, vomiting, gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastroesophageal reflux (GERD), motility disorders and delayed gastric emptying such as postoperative or -9EN 299411 B6 diabetic gastroparesis, diabetes, gastric ulcers, diarrhea, and other diseases such as gynecological diseases, osteoporosis, inflammation, infections such as infection caused by bacteria, fungi, protozoa and viruses - H1V-1 or H1V-2 infection, pain, cancer, chemotherapy-induced damage, tumor invasion, immune disorders, urinary retention, asthma, allergy, arthritis 5 benign prostatic hypertrophy, endotoxin shock, sepsis and complicated diabetes mellitus. 4. A composition according to claim 3, wherein the active agent is an active agent for the treatment of CNS disorders. ío Composition according to claim 4, characterized in that the active ingredient is fluvoxamine or flesinoxane or a pharmaceutically acceptable salt thereof. 6. A formulation according to claim 5, wherein the active ingredient is flesinoxane monohydrochloride (N- [2- [4 - [(2R) -2,3-dihydro-2- (hydroxymethyl) -1,45 benzodioxine-5 monohydrochloride)]. -yl] -1-piperazinyl] ethyl] -4-fluoro - (+) - benzamide). 7. A composition according to claim 3, wherein the active ingredient is an active ingredient for the treatment of cardiovascular diseases. 20 May The formulation according to claim 7, wherein the active agent is tedisamil or propranolol or a pharmaceutically acceptable salt thereof. Composition according to claim 8, characterized in that the active ingredient is tedisamil sesquifumarate (N, N'-dicyclopropylmethyl-9,9-tetramethylene-3,7-diaza-bicyclo [3.3.1] nonane [1, 2] 5] 25 hydrogen fumarate). 10. A composition according to claim 3, wherein the active ingredient is an active ingredient for hormone replacement therapy. 30 11. A formulation according to claim 10, wherein the active ingredient is dydrogesterone, estradiol or conjugated estrogens. A method for producing a composition according to any one of claims 1 to 11, characterized in that: (1) compress the core of a mixture comprising one or more active ingredients and a high or medium viscosity hydroxypropylmethylcellulose (HPMC) and a high or medium viscosity hydroxyethylcellulose (HEC) in a ratio of HPMC / HEC = 1 / 0.85 to 1 / 1.2, and optionally a low viscosity HPMC, wherein the ratio of high or medium viscosity HPMC / low viscosity HPMC = 1 / 0.01 to 1 / 0.2, which provides sustained release of the active ingredient, 40 substantially with zero order kinetics, and (2) optionally, coating the core.